The primary purpose of this Mentored Clinical Scientist Development Award is to prepare the applicant for a career as an independent investigator in cardiology. The applicant proposes to acquire additional skills in molecular biology and somatic gene transfer in the context of a project that builds upon his previous experience in studying apoptosis and signal transduction. Cardiomyocyte apoptosis has been documented in many clinically pathways conditions including human and experimental ischemic heart disease. However, the intracellular pathways controlling cardiomyocyte cell death and the functional contribution of apoptosis to cardiac disease pathogenesis, have not been delineated. The goals of this proposal are to understand the role of PI 3-kinase signaling pathways in blocking cardiomyocyte apoptosis and the functional significance of cardiomyocyte apoptosis in an experimental model of ischemic heart disease. Insulin-like growth factor-I (IGF-I) has beneficial effects on both cardiomyocyte function and survival. Binding of IGF-I to its receptor initiates a complex array of signaling events. In many systems, activation of phosphatidylinositol (PI) 3-kinase is critical to the ability of IGF-I to block apoptosis. Recently, the serine-threonine kinase, Akt, has been identified as both necessary and sufficient for the ability of PI 3-kinase to block apoptosis in neurons. This proposal is based on three hypotheses: 1) that apoptosis in myocardium contributes significantly to infarct size and cardiac dysfunction in ischemia-reperfusion (IR), 2) that the benefits of IGF-I treatment in IR are mediated through local inhibition of cardiac apoptosis, and 3) that IGF-I inhibits cardiomyocyte apoptosis through activation of PI 3-kinase and Akt. To test these hypotheses, we will use adenoviral vectors to express wild-type and mutant forms of specific signaling molecules in cardiomyocytes in vitro and in vivo. In Specific Aim 1, we examine the role of these pathways on cardiomyocyte survival and function in an in vitro model of transient hypoxia. In Specific Aim 2, we will examine the effects of these molecules on cardiomyocyte apoptosis and function in vivo. In Specific Aim 3, we will study the role of the same pathways in cardiac apoptosis and function in a rat model of IR. Understanding the role of specific signaling pathways in cardiomyocyte apoptosis and developing approaches to local modulation of these pathways through somatic gene transfer, may provide novel therapeutic approaches for the management of many clinically important disorders.